Huybrechts Krista F, Bateman Brian T, Hernández-Díaz Sonia
Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Pharmacoepidemiol Drug Saf. 2019 Jul;28(7):906-922. doi: 10.1002/pds.4789. Epub 2019 May 10.
Because preapproval clinical trials typically exclude pregnant women, the evidence on drug safety during pregnancy required to inform drug labeling must come from postapproval controlled observational studies. Common designs have included pregnancy registries and case-control studies. Recently, pregnancy cohorts nested within healthcare utilization databases are increasingly being used. Despite clear advantages, these databases share some important limitations that may threaten the validity of studies emerging from them.
This paper describes the distinctive methodological aspects of conducting drug safety studies in healthcare utilization databases with special emphasis on design and analytic approaches to minimize biases.
We describe considerations for study design, cohort definition, and follow-up. We then address issues related to exposure ascertainment based on prescription fills, including the importance of the etiologically relevant window and of properly accounting for preterm births. This is followed by a discussion of advantages and challenges when ascertaining maternal and infant outcomes based on secondary data. We then explore useful approaches to address confounding within the context of pregnancy research and of the potential for selection bias when restricting the cohort to live births. Finally, we consider issues related to external validity and statistical significance. The examples are mainly drawn from a pregnancy cohort nested in the Medicaid Analytic Extract.
The approaches presented provide guidance regarding the important methodological considerations that need to be attended to in order to generate valid, minimally biased risk when using large healthcare utilization databases for drug safety surveillance in pregnancy.
由于批准前的临床试验通常将孕妇排除在外，因此用于指导药品标签的孕期药物安全性证据必须来自批准后的对照观察性研究。常见的设计包括妊娠登记和病例对照研究。最近，嵌套在医疗保健利用数据库中的妊娠队列越来越多地被使用。尽管有明显优势，但这些数据库存在一些重要局限性，可能会威胁到从中得出的研究的有效性。
本文描述了在医疗保健利用数据库中进行药物安全性研究的独特方法学方面，特别强调了设计和分析方法以尽量减少偏差。
我们描述了研究设计、队列定义和随访的注意事项。然后我们讨论了基于处方配药确定暴露情况的相关问题，包括病因相关窗口的重要性以及正确考虑早产情况。接下来讨论了基于二手数据确定母婴结局时的优势和挑战。然后我们探讨了在妊娠研究背景下解决混杂问题的有用方法，以及将队列限制为活产时选择偏倚的可能性。最后，我们考虑了与外部有效性和统计学显著性相关的问题。这些例子主要来自嵌套在医疗补助分析提取物中的一个妊娠队列。
所提出的方法为在使用大型医疗保健利用数据库进行孕期药物安全性监测时，为了产生有效、偏差最小的风险而需要关注的重要方法学考虑提供了指导。
